Finding the Optimal Fluid Strategies for Sepsis

Marilynn Larkin

June 30, 2023

A new review offers evidence-based strategies for improving sepsis outcomes with appropriate doses of intravenous (IV) fluid therapy at each stage of treatment.

The document offers guidance on the four forms of fluid use; assessing whether IV fluid administration is indicated; and fluid therapy goals, timing, type, and other clinical parameters. The recommendations are based on a literature search that included 28 randomized clinical trials (RCTs), seven secondary analyses of RCTs, 20 observational studies, five systematic reviews or meta-analyses, one scoping review, one practice guideline, and 14 references from a reference review.

Dr Fernando Zampieri

"Our review highlights that crystalloids should remain the standard of care for most critically ill patients, especially during early resuscitation," Fernando G. Zampieri, MD, PhD, assistant adjunct professor of critical care medicine at the University of Alberta and Alberta Health Services in Edmonton, Alberta, Canada, told Medscape Medical News. "In particular, starches should not be used in critically ill patients. Balanced solutions might be better for most patients, except for patients with traumatic brain injury, where 0.9% saline is recommended."

The review was published online June 13 in the Journal of the American Medical Association.

Four Therapeutic Phases

Approximately 20%-30% of patients admitted to an intensive care unit have sepsis, and fluid therapy is a key component of their treatment. Although IV fluid can increase cardiac output and blood pressure, maintain or increase intravascular fluid volume, and deliver medications, too much fluid or the wrong type of fluid may cause harm.

"Deciding which type of fluid is the best for a patient [with sepsis] can be challenging," said Zampieri.

Fluid therapy can be conceptualized as encompassing four overlapping phases from early illness through resolution of sepsis, according to the review. These phases include resuscitation (rapidly administering fluid to restore perfusion), optimization (assessing risks and benefits of additional fluids to treat shock and ensure organ perfusion), stabilization (using fluid therapy only when there is a signal of fluid responsiveness), and evacuation (eliminating excess fluid accumulated during treatment).

The review described the studies that underpin its key recommendations for management in these phases. Three RCTs included 3723 patients with sepsis who received 1-2 L of fluid. They found that goal-directed therapy with administration of fluid boluses to attain a central venous pressure of 8-12 mm Hg, vasopressors to attain a mean arterial blood pressure of 65-90 mm Hg, and red blood cell transfusions or inotropes to attain a central venous oxygen saturation of at least 70% did not decrease mortality, compared with unstructured clinical care (24.9% vs 25.4%, P = .68).

One RCT with 1563 patients with sepsis and hypotension who received 1 L of fluid found that favoring vasopressor treatment did not improve mortality, compared with further fluid administration (14.0% vs 14.9%, P = .61).

In another RCT, among 1554 patients with septic shock who were treated in the intensive care unit with at least 1 L of fluid, restricting fluid administration in the absence of severe hypoperfusion did not reduce mortality, compared with more liberal fluid administration (42.3% vs 42.1%, P = .96).

An RCT of 1000 patients with acute respiratory distress during the evacuation phase found that limiting fluid administration and giving diuretics improved the number of days alive without mechanical ventilation, compared with fluid treatment to attain higher intracardiac pressure (14.6 vs 12.1 days, P < .001).

This study also found that hydroxyethyl starch significantly increased the incidence of kidney replacement therapy, compared with saline (7.0% vs 5.8%, P = .04), Ringer lactate, or Ringer acetate.

Ultrasonography Lacks Validation  

The authors summarized the key concerns about fluid therapy. Fluid therapy should be initiated for patients with evidence of sepsis-induced hypoperfusion who are likely to have increased cardiac output with fluid administration, they wrote. Fluid administration should be discontinued when evidence of hypoperfusion resolves, the patient no longer responds to fluid, or the patient shows evidence of fluid overload.

Balanced solutions should be selected over 0.9% saline for fluid therapy, according to the review. Hydroxyethyl starches should not be used.

Fluid removal should be considered after the resuscitation and optimization phases and when a patient has stabilized, the authors wrote. Diuretics are first-line therapy to facilitate fluid elimination.

Kidney replacement therapy may be considered for patients with severe acute kidney injury who have complications from fluid overload and are unresponsive to diuretic therapy.

"The use of ultrasonography as a bedside tool to guide fluid resuscitation is promising but lacks validation in robust randomized controlled trials," said Zampieri. "Point-of-care ultrasound may be useful to assess causes of shock and [helping to exclude] a life-threatening diagnosis at presentation, such as cardiac tamponade."

Pending the emergence of further evidence, the authors suggest that clinicians prescribe fluids judiciously, preferably at aliquots followed by frequent reassessment. "Defining a resuscitation target (such as capillary refill time or lactate, among others) and performing fluid challenges to correct them while no overt signs of fluid overload (such as pulmonary edema) occur is a common practice that is also sustained by clinical research," said Zampieri.

He added that the review's recommendations are based on research conducted mainly in high-income settings, and that generalizability will depend on factors such as local standards of care and resource availability.

"Our review provides an overall guidance, but caution is warranted before extrapolating the suggestion to every possible clinical scenario," he concluded.

Fluids as Drugs

Commenting on the review for Medscape, Hernando Gomez, MD, MPH, an associate professor of critical care medicine at the University of Pittsburgh, Pittsburgh, Pennsylvania, said, "I agree with the conclusions and commend the authors for this very practical revision of the literature." Gomez was not involved in the review.

Dr Hernando Gomez

"I would like to stress the point, however, that although fluids can be harmful, particularly when not indicated and when used in excess, fluid resuscitation in patients with sepsis who have evidence of hypoperfusion is paramount," he said.

"The association between fluid accumulation and poor outcomes is truly a Goldilocks problem, often described in the literature as a 'U' shape, where too little fluid (ie, a very restrictive strategy) or too much fluid (ie, use in excess and in discordance with the patient's needs) can be harmful," said Gomez.

Furthermore, every strategy to assess fluid responsiveness has limitations. "It is key that clinicians resist the temptation to dismiss these limitations, because decisions made on flawed data are as dangerous as not assessing fluid responsiveness in the first place," he said.

Based on the evidence, clinicians should "think of fluids as a drug and carefully assess risks and benefits before deciding to administer fluids to their patients," Gomez added. It is also important to separate the question "Does my patient need fluids?" from the question "Is my patient fluid-responsive?"

"These are two different questions that often get conflated," Gomez said. "If a bolus of fluid given to a patient who needs fluids and is fluid-responsive does not improve tissue perfusion, then fluids should not be given."

No funding was reported for the review. Zampieri reports receiving fluids and logistics from Baxter Hospitalar during the conduct of the BaSICS trial, personal fees from Bactiguard for statistical consulting and from Baxter for participating in an advisory board, grants from Ionis Pharmaceuticals outside the submitted work, and serving as lead investigator of the BaSICS trial. Gomez reports no relevant financial relationships.

JAMA. Published online June 13, 2023. Abstract.

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